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Kristina D Lamens, Meredith C Rogers, Justin T Tometich, Timothy W Hand, John V Williams, Uncharted Territory: The CD4+ T cell response to human metapneumovirus, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 198.2, https://doi.org/10.4049/jimmunol.202.Supp.198.2
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Abstract
Human metapneumovirus (HMPV) is a leading cause of lower respiratory tract infection in pediatric and immunocompromised populations. Clearance of respiratory viruses including HMPV relies primarily on the destruction of infected cells by cytotoxic CD8+ T cells. However, signals provided by CD4+ helper T cells significantly impact the magnitude and effectiveness of CD8+ T cells. Using a mouse model of acute infection, we performed an in-depth analysis of CD4+ helper T cells in the immune response to HMPV. We identified and validated an immunodominant CD4+ T cell epitope in C57BL/6 mice and constructed the first MHC-II tetramer for HMPV. Kinetic analysis showed that the percentage of CD44+tetramer+ cells in the lung peaked at day 10 post-infection. Ex vivo peptide stimulation of pulmonary T cells revealed that most virus-specific CD4+ T cells produced IFNγ, followed by a small but consistent population of IL-17a producing cells. To determine the contribution of CD4+ T cells in the primary immune response to HMPV, CD4+ T cells were antibody-depleted prior to infection. Depletion of CD4+ T cells exacerbated infection-induced CD8+ T cell impairment, led to enhanced PD-1 expression on virus-specific CD8+ T cells, and delayed viral clearance. Next, global PD-1−/− mice were infected with HMPV to further explore the role of PD-1. Both CD4+ and CD8+ T cells displayed improved functionality in HMPV-infected PD-1−/− mice, suggesting that PD-1-mediated impairment following respiratory virus infection affects CD4+ as well as CD8+ T cells. Further characterization of virus-specific CD4+ helper T cells, their regulation by PD-1, and their role in CD8+ T cell impairment will provide new insights that aid in the design of effective vaccines against HMPV.
